Isoxazolium Salts Research Articles

Synthetic Study on Lactonamycins, Part 2: Stereoselective Access to ABCD-Ring System

Toward a stereoselective total synthesis of the lactonamycins, we recently reported an approach to the DEF-ring system. Here we report a model study for constructing the ABCD-ring system, revealing a viable approach through (1) construction of the C-ring by asymmetric benzoin cyclization, (2) introduction of an angular hydroxy group through oxidation of an isoxazolium salt, and (3) construction of the AB rings through a ring-opening/closing sequence.

Light-Activatable, 2,5-Disubstituted Tetrazoles for the Proteome-wide Profiling of Aspartates and Glutamates in Living Bacteria.

Covalent inhibitors have recently seen a resurgence of interest in drug development. Nevertheless, compounds, which do not rely on an enzymatic activity, have almost exclusively been developed to target cysteines. Expanding the scope to other amino acids would be largely facilitated by the ability to globally monitor their engagement by covalent inhibitors. Here, we present the use of light-activatable 2,5-disubstituted tetrazoles that allow quantifying 8971 aspartates and glutamates in the bacterial proteome with excellent selectivity. Using these probes, we competitively map the binding sites of two isoxazolium salts and introduce hydrazonyl chlorides as a new class of carboxylic-acid-directed covalent protein ligands. As the probes are unreactive prior to activation, they allow global profiling even in living Gram-positive and Gram-negative bacteria. Taken together, this method to monitor aspartates and glutamates proteome-wide will lay the foundation to efficiently develop covalent inhibitors targeting these amino acids.

Ruthenium-Catalyzed Asymmetric Reduction of Isoxazolium Salts: Access to Optically Active Δ4-Isoxazolines

A tethered MsDPEN-ruthenium catalyst reduces a series of isoxazolium salts, affording optically active Δ4-isoxazolines in moderate to good yields and enantioenrichment. The redundancy of heating or high pressures allowed for chemoselective reduction with no subsequent heterocyclic ring opening. Our results reinforce our understanding of the workings of these Noyori-class catalysts.

Covalent Probe Finds Carboxylic Acid

In this issue of Cell Chemical Biology, Martín-Gago etal. (2017a) disclose a new strategy for the selective covalent targeting of binding site carboxylic acids within the proteome using the isoxazolium salt as a warhead. This discovery paves the way for developing new protein ligation methods as well as covalent drug candidates.

Covalent Protein Labeling at Glutamic Acids

Covalent labeling of amino acids in proteins by reactive small molecules, in particular at cysteine SH and lysine NH groups, is a powerful approach to identify and characterize proteins and their functions. However, for the less-reactive carboxylic acids present in Asp and Glu, hardly any methodology is available. Employing the lipoprotein binding chaperone PDE6δ as an example, we demonstrate that incorporation of isoxazolium salts that resemble the structure and reactivity of Woodward's reagent K into protein ligands provides a novel method for selective covalent targeting of binding site carboxylic acids in whole proteomes. Covalent adduct formation occurs via rapid formation of enol esters and the covalent bond is stable even in the presence of strong nucleophiles. This new method promises to open up hitherto unexplored opportunities for chemical biology research.

Pleospdione, A Tricyclic Natural Product with Dense Oxygenation at the A-Ring: Total Synthesis and Incongruity of the Originally Assigned Structure and its C3-Epimer

Abstract Previously we developed a promising synthetic approach to complex polycyclic natural products, including aromatic polyketides derived from the type-II polyketide biosynthesis. The approach consists of three key steps; (1) cycloaddition or cyclocondensation of nitrile oxide for assembling the carbon skeleton having an isoxazole as a 1,3-diketone equivalent, (2) benzoin cyclization for stereoselective ring fusion with an angular hydroxy group, and (3) oxidation of isoxazolium salt for installing an additional angular hydroxy group in stereoselective manner. As a synthetic exercise to highlight the utility of this approach, the first total syntheses of the proposed structure of pleospdione (1) and its C3-epimer (3-epi-1) have been achieved. The synthesis has proved the efficiency of the strategy as an entry into polyketide-derived complex architectures. At the same time, it was revealed that neither 1 nor 3-epi-1 represent the true structure of the natural product by incongruity of the NMR spectra.

Silylated azolium salts and their applications in the synthesis of azolines and β-enaminoketones bearing allyl-, vinyl-, and acylsilane or α-silylketone units

Differently silylated 3- or 4-isoxazolines and 3-pyrazolines, bearing versatile vinyl- or allylsilane moieties in various positions of the heterocyclic system, have been synthesized starting from new silylazolium salts by reduction with metal complex hydrides or alkylation with organolithium reagents. On the other hand, the reductive ring-opening of silylated isoxazolium salts with lithium dimethylcuprate led to interesting β-enamino acylsilanes and α′-silylmethyl-β-enaminoketones. These polysynthetic equivalents are useful building blocks in organic synthesis.

ChemInform Abstract: Formation of α‐Hydroxy‐β‐diketones Through Hydroxylation of Isoxazolium Salts: Stereoselective Approach to Angular cis‐Diols in Polycyclic Systems.

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Formation of α‐Hydroxy‐β‐diketones through Hydroxylation of Isoxazolium Salts: Stereoselective Approach to Angular cis‐Diols in Polycyclic Systems

Formation of α‐Hydroxy‐β‐diketones through Hydroxylation of Isoxazolium Salts: Stereoselective Approach to Angular <i>cis‐</i>Diols in Polycyclic Systems

Formation of α‐Hydroxy‐β‐diketones through Hydroxylation of Isoxazolium Salts: Stereoselective Approach to Angular cis‐Diols in Polycyclic Systems

Formation of α‐Hydroxy‐β‐diketones through Hydroxylation of Isoxazolium Salts: Stereoselective Approach to Angular <i>cis‐</i>Diols in Polycyclic Systems

The reactions of 5‐aryl‐2,3‐dimethylisoxazolium salts with aromatic aldehydes

AbstractThe reactions of the 3‐methyl group in 5‐aryl‐2,3‐dimethylisoxazolium tetrafluoroborates with aromatic aldehydes, in the presence of piperidine were studied. Isoxazolium salt reactivity is independent of the phenyl group substituent at C‐5 on the isoxazolium salt ring. However, it does depend on the aldehyde structure.

Synthèse d'isoxazoles substitués en α de l'azote par une chaine alkyle ou alcényle

Several syntheses of special isoxazoles bearing a long alkyl or alkenyl side chain in the α position of the nitrogen are presented. A very convenient route in the case of an alkyl side chain is the classical 1,3-dipolar cycloaddition of a nitrile-oxide to a vinyl acetate. Although it is a rather long approach, the reaction of hydroxylamine with enone-epoxides represents a new and unequivocal method compatible with alkenyl side chains. The isomerisation of the easily synthesized isoxazoles bearing such substitutents α to the oxygen, by the reaction of their isoxazolium salts with hydroxylamine, is a fast and general method. Another very convenient access to "α-N substituted" isoxazoles is the coupling of magnesium compounds with 3-bromomethyl 5-methyl isoxazole. Keywords: isoxazoles, substitution in the α position of nitrogen.

ChemInform Abstract: Formation of 2‐Substituted 2‐Isoxazolinium Salts by the Reaction of 1,1,2,2‐Tetrasubstituted Cyclopropanes with NOBF4.

AbstractThe tetrasubstituted cyclopropanes (I) react with nitrosyl tetrafluoroborate (II) to give the isoxazolium salts (III) or (V) and (VI) which are reduced with lithium alanate, forming the isoxazoline (IV) or a mixture of the regioisomers (VII) and (VIII).

Addition of Organocuprates to Ketoketenimines. Synthesis of β-enaminoketones

Abstract Base-induced ring cleavage of 3-unsubstituted isoxazolium salts followed by reaction of the resulting ketoketenimine with organocuprates affords asymmetric β-enaminoketones in high yields.

ChemInform Abstract: The Naphth(1,2‐d)isoxazolium Cation Reactions with Nucleophilic Species.

AbstractThe isoxazolium salt (I) is cleaved with sodium sulfide, sodium methoxide (III), or the carboxylic acids (V) to produce the derivatives (II), (IV), and (VI) of 2‐hydroxynaphthalene‐1‐carboxylic acid.

Reaction of isoxazoles and isoxazolium salts with organometallic reagents. Synthesis of dihydroisoxazoles

2,3- 2,5-, and 4,5-Dihydroisoxazoles have been selectively synthesized by reaction of isoxazoles with organo-lithium, -magnesium, and -aluminium reagents. Moreover, the reaction of benzoisoxazolium salts with highly basic organolithium compounds leads to phenylaziridines resulting from an unusual ring cleavage-closure process. A mechanism which accounts for all the experimental results is also given.

Cathodic reduction of isoxazolium salts

The oathodic reduction of N-alkylisoxazolium salts gives β-enaminoketones in high yields. A logical reaction route is given.

The Reactions of 3-Unsubstituted Isoxazolium Salts with 1,2-Dinucleophiles. Synthesis of 4-Functionalized 3-Aminoisoxazoles and 3-Aminopyrazoles

The Reactions of 3-Unsubstituted Isoxazolium Salts with 1,2-Dinucleophiles. Synthesis of 4-Functionalized 3-Aminoisoxazoles and 3-Aminopyrazoles

Synthesis of 3- and 4-Isoxazolines by Reduction of 4-Functionalized Isoxazolium Salts with Complex Metal Hydrides

Synthesis of 3- and 4-Isoxazolines by Reduction of 4-Functionalized Isoxazolium Salts with Complex Metal Hydrides

ChemInform Abstract: ISOXAZOLE CHEMISTRY SINCE 1963

Publisher Summary This chapter discusses the developments in the chemistry of isoxazoles. The developments in this field include further application of the cycloaddition of nitrile oxides in the synthesis of isoxazoles, the use of isoxazolium salts in peptide synthesis, syntheses involving the products of reductive cleavage of isoxazoles as intermediates, and annelation reactions via deprotonation of alkylisoxazoles. The synthetic routes to isoxazoles may be classified according to the number of isoxazole ring atoms in each component synthon, the type of ring atom in each component, and the chemical class to which each component belongs. The various reactions of isoxazoles are also discussed. These include reactions with electrophiles, reactions of isoxazoles and isoxazolium salts with nucleophiles, and special reactions of side chains on isoxazoles. The physicochemical studies on isoxazoles are discussed. These include theoretical and structural studies, nuclear magnetic resonance spectroscopy, and prototropic tautomerism of isoxazole derivatives. Various biologically active isoxazoles are tabulated.